Progress in understanding how neuronal dysfunction can lead to nervous system disorders has highlighted the central role played by trophic factors in modulating brain function. A substantial body of pre-clinical and clinical studies has suggested that a primary deficit in trophic support is involved in the etiology of depression. Furthermore, antidepressants appear to exert their effects by elevating levels of trophic factors. This class of molecules frequently exhibit multi-functional effects, influencing both neurons and vasculature via their neurotrophic and angiogenic effects. In comparison to the significant attention that has been directed towards understanding neural actions of neurotrophins, there is sparse knowledge of the mechanism of action of multi-functional trophic factors. Erythropoietin (EPO) a naturally occurring hormone and trophic factor, widely used to treat anemia, has recently been shown to exert robust neurotrophic and angiogenic effects in the brain. Moreover, peripheral administration is sufficient to rescue neuronal damage in several animal models. These trophic effects appear to be independent of EPOs hematopoietic role. In well characterized rodent behavioral models of antidepressant action we have observed EPO to produce antidepressant effects. Interestingly, human studies have also demonstrated that EPO produces cognitive enhancing and antidepressant- like effects. However, the mechanism whereby these effects are produced is not understood. Also, the use of an erythropoietic molecule to produce trophic effects leads to hematological complications in non-anemic patients. We propose to dissociate the erythropoietic effects from the neurotrophic and angiogenic effects by employing biochemically engineered non-erythropoietic derivatives that retain the trophic properties of EPO. Employing conditional, receptor knockout mice we will further dissect the neuronal and endothelial actions at the molecular, cellular and behavioral levels. The results of these studies will provide new insight towards developing novel trophic action based therapeutics and will be particularly applicable to disorders that involve both neuronal and vascular dysfunction.